CN108024995A - 包含塞来昔布及曲马多的药剂学组合物 - Google Patents
包含塞来昔布及曲马多的药剂学组合物 Download PDFInfo
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- CN108024995A CN108024995A CN201680041339.3A CN201680041339A CN108024995A CN 108024995 A CN108024995 A CN 108024995A CN 201680041339 A CN201680041339 A CN 201680041339A CN 108024995 A CN108024995 A CN 108024995A
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Abstract
本发明涉及包含塞来昔布和曲马多的复合剂。本发明的特征在于,尽管将两种不同的活性成分以单一剂型而剂型化,但通过新处方使各种药物的释放模式被设计为最优于各种药物针对疼痛的协同效果的表现。
Description
技术领域
本发明涉及包含已知为选择性COX-2抑制剂的塞来昔布和作为阿片类镇痛剂的曲马多的药剂学组合物。
背景技术
[疼痛]
根据国际疼痛研究协会(International Association for the Study of Pain)的定义,疼痛是指实际或潜在的组织损伤引起的令人不快的感觉和情绪上的感受。疼痛的原因大可分为因身体组织或耐性组织的损伤或炎症而引起的感知情况,以及神经受损后产生的神经病症性情况。其中,所报告的感知情况的发病机理如下。
当组织被损伤时,损伤刺激(stimulus)本身通过使有髓鞘(A-delta)及C-伤害性感受器(C-nociceptor)兴奋,以传递痛觉。随后,从受损的组织细胞及末梢神经的末端等游离出缓激肽(bradykinin)、5-羟色胺(serotonin)、K+、H+及P物质(substance P)等。在这个过程中,在受损部位的末梢伤害性感受器产生敏化(sensitization),使阈值降低,并创建多发性兴奋,这种痛觉信息通过痛觉神经传送到脊髓,并且其上升到脊髓的上部并被处理,从而可引发感知疼痛的痛症。并且,当组织受到损伤时,细胞膜被破坏并活性化磷脂酶A(phospholipase A),则生成花生四烯酸(arachidonic acid),这可通过环氧酶(cyclooxygenase,COX)路径合成前列腺素(prostaglandin),此前列腺素使末梢伤害性感受器敏化,以引发疼痛(有关疼痛的机理的研究,BioWave Vol.8 No.3 2006)。
[疼痛相关药剂]
对于疼痛利用镇痛剂来降低其强度,有时由于慢性疼痛可引起抑郁症,因而时而并用抗抑郁剂。代表性的镇痛剂有作为阿片性镇痛剂的阿片类镇痛剂(opioid analgesic)和作为非阿片性镇痛剂的非甾体抗炎药(non-steroidal anti-inflammatory drug,NSAID)。
阿片类镇痛剂作为阿片类化合物,已知通过与阿片受体(opioid receptor)结合阻断P物质或谷氨酸(glutamate)等的神经递质的分泌,以抑制痛觉信号传递至大脑,从而具有强力的抑制疼痛作用。但是,最近随着有关长期服用阿片类镇痛剂而导致的药物中毒、骨折风险、心机梗塞及性功能障碍等的副作用的报告,减少其服用量的必要性已成为一个问题。
已知非甾体抗炎药是通过抑制环氧酶来阻碍前列腺素的合成,从而进行消炎作用即抑制疼痛作用。最初,使用了布洛芬、双氯芬酸或萘普生等,但随着报道出其还抑制COX-1,从而有可能引发胃肠道疾病的问题,之后作为COX-2选择性抑制剂的塞来昔布等备受瞩目。但是,由于这仅仅是借助消炎作用来间接抑制疼痛,其阵痛效果不如上述阿片类镇痛剂。
[塞来昔布及曲马多的联合用药]
作为可增加COX-2选择性抑制剂的阵痛效果的代替方案,韩国授权专利公报第10-0444195关注了基于COX-2选择性抑制剂与阿片类镇痛剂的联合用药的协同效果。根据该文献,对与COX-2选择性抑制剂和阿片类镇痛剂有关的等效剂量替代模型(equieffectivedose substitution model)及曲线回归进行分析的结果,当组合COX-2抑制剂与阿片类镇痛剂时,出现了意想不到的阵痛活性的增加,因此与对相同的疼痛独立使用两种药剂的情况相比,可减少其服用量,从而预计可减轻各药剂引起的副作用的种类及程度。
韩国公开专利公报第10-2012-0089287号关注了曲马多和塞来昔布在解决大剂量及反复使用阿片类镇痛剂的副作用的协同效果。根据该文献,曲马多和塞来昔布的组合在治疗严重疼痛至剧烈疼痛,尤其在具有炎性要素的疼痛方面是有效的,具体地,指出对坐骨神经痛(sciatica)、五十肩(frozen shoulder)或中枢敏化[central sensitization,例如,中枢性疼痛综合症(central pain syndrome)]等的仅靠单纯的单一药剂其效果不充分的疾病、症状或相关疼痛有用。
[塞来昔布及曲马多各自的制剂化时的特征]
塞来昔布是由下式[式1]表示的化合物,其化学式为4-[5-(4-甲基苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺(4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfona mide)。
[式1]
塞来昔布作为难溶性药物,其具有难以制剂化的特征。为提高塞来昔布的生物体利用率,在韩国授权专利公报第10-0501034号中试图了粒子的微粒化,在韩国授权专利公报第10-1455901号中,利用了作为表面活性剂(所谓的增溶剂)的泊洛沙姆,在韩国授权专利公报第10-1237646号中,利用了将水溶性高分子和表面活性剂修饰于塞来昔布的粒子表面的固态分散体技术。
曲马多(tramadol)是由下式[式2]表示的化合物,其化学式为2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)环己醇(2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol)。
[式2]
曲马多作为水溶性药物,主要用于慢性疼痛,因此为提高服用的便利性,将其制剂成缓释型是有效的。为了将曲马多制剂化为缓释型,在韩国授权专利公报第10-1455741号中,通过与水接触形成水凝胶来添加可控制药物有效成分的释放的凝胶形成物质,例如,羟丙基纤维素、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠等的纤维素衍生物或羧乙烯聚合物。
发明内容
解决的技术问题
本发明人关注了塞来昔布与曲马多组合的对于疼痛的协同效果,并试图将上述两种不同的活性成分配制成单一剂型,以进一步提高服用各药物的便利性。
为此,首先考虑的是各种药物的释放模式的设计。许多反复实验结果显示,优选地,塞来昔布以速释型区域来存在,曲马多以缓释型区域来存在。
接下来考虑了实现上述释放模式的制剂的形态,并且认为其形态可适用多种类型。例如,可使用干压包衣片,由内核和外层构成,上述内核由缓释型区域形成,上述外层由速释型区域形成;胶囊,包含由缓释型区域形成的粒子、颗粒、微粒或片剂和由速释型区域形成的粒子、颗粒、微粒或片剂;或多层片剂,通过层压由缓释型区域形成的层和由速释型区域形成的层形成。
其中,作为优选一实施例,使用多层片剂后,层压已知的曲马多的缓释型基质和塞来昔布的速释型基质,之后对各种药物的释放模式进行了实验,发现其在塞来昔布的目标溶出达成方面存在问题。
为此,本发明人进行了大量的反复实验,以制备通过单一剂型实现塞来昔布和曲马多的目标释放模式的新配方,其结果完成了本发明。
技术方案
本发明通过以下手段解决了上述问题。
(1)包含第一区域以及第二区域的药剂学组合物中,上述第一区域包含塞来昔布,上述第二区域包含曲马多,上述药剂学组合物的特征在于,第二区域包含非水溶性高分子及蜡类似脂质。
(2)上述(1)的药剂学组合物的特征在于,第一区域包含选自水溶性高分子、表面活性剂及糖类中的一种以上。
(3)上述(2)的药剂学组合物的特征在于,水溶性高分子为选自羟丙基纤维素、羟丙基甲基纤维素及乙烯基吡咯烷酮乙酸乙烯酯共聚物中的一种以上。
(4)上述(2)或(3)的药剂学组合物的特征在于,表面活性剂包含选自聚氧甘油酯、聚氧乙烯山梨糖醇酐脂肪酸酯、月桂基硫酸钠、甘油基脂肪酸酯、脂肪酸聚乙二醇甘油酯、二乙二醇单乙醚及蔗糖脂肪酸酯中的一种以上。
(5)上述(2)至(4)中任一项所述的药剂学组合物的特征在于,相对于第一区域的总重量,包含0.1~20重量百分比的水溶性高分子和表面活性剂。
(6)上述(2)至(5)中任一项所述的药剂学组合物的特征在于,糖类包含选自甘露醇、麦芽糖醇、乳糖醇、核糖醇、肌醇、木糖醇、麦芽三糖醇及葡萄糖中的一种以上。
(7)上述(2)至(6)中任一项所述的药剂学组合物的特征在于,相对于第一区域的总重量,包含10~50重量百分比的糖类。
(8)上述(1)至(7)中任一项所述的药剂学组合物的特征在于,蜡类似脂质包含选自硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸棕榈酸甘油酯、脂肪酸聚乙二醇甘油酯、二乙二醇单乙醚、单辛酸甘油酯及氢化蓖麻油中的一种以上。
(9)上述(1)至(8)中任一项所述的药剂学组合物的特征在于,非水溶性高分子包含选自纤维素类中的一种以上。
(10)上述(1)至(9)中任一项所述的药剂学组合物的特征在于,相对于第二区域的总重量,包含1~60重量百分比的蜡类似脂质及非水溶性高分子。
(11)上述(1)至(10)中任一项所述的多层片的特征在于,以另外的层形成第一区域和第二区域,并将其层压。
发明的效果
作为口服用固体复合剂的本发明,各药物的释放模式与分开服用市售的塞来昔布口服用固体单剂和曲马多口服用固体单剂时相同。具体而言,本发明作为将塞来昔布和曲马多制剂化为一个单一剂型的复合剂,作为难溶性药物的塞来昔布由增容的速释型形成,曲马多由缓释型形成,通过最小化剂型内的各药物的相互作用,从而将其设计为即使每天仅服用一次也可以使各种药物互补并持续发挥作用。
此外,根据本发明的多层片剂具有优秀的硬度和层间粘合性,因此易于包装、搬运及处理,并且由于封盖(capping)或层压(laminating)等困难少,因此适合大规模生产。
附图说明
图1至图13为示出各实施例的溶出模式。
具体实施方式
本发明涉及口服用固体复合剂,其包含由速释型组成的塞来昔布区域和由缓释型组成的曲马多区域。当需要显示不同释放模式的两种以上药物被制剂化为单一剂型时,重要的是设计成任何区域的组成都不影响其他区域中药物的释放模式。尤其,当将塞来昔布制剂化为单剂时,因药物本身为极难溶性药物,而需要加入特殊的增溶手段,并且塞来昔布是一种非常灵敏且难以达到令人满意的溶出的药物。
因此,尽管进行了预期,但当使已知的缓释型曲马多区域与塞来昔区域简单接触时,曲马多区域的缓释型组成是否对塞来昔布的释放模式产生负面影响,即使在塞来昔布区域内加入了增溶手段,但是塞来昔布的释放模式还是令人不满意。
因此,在本发明中,集中于可最小化缓释型曲马多区域的组成对塞来昔布的释放模式的影响的曲马多区域的处方和塞来昔布区域的处方,以下将对其进行说明。
[定义]
“塞来昔布”及“曲马多”是指服用后在代谢过程中可显示出公知的塞来昔布及曲马多的药理学活性的形态,作为非限制性的例子,均呈现出游离酸/碱、盐、共晶、外消旋体和前体药物等。例如,“曲马多”可以解释为盐酸曲马多。
“增溶手段”是指用于难溶性药物的溶出提高法中的已知的方法之一,作为非限制性的例子,作为塞来昔布的已知的增溶手段包括粒子的微粒化、泊洛沙姆的配合和固体分散体化。
“水溶性高分子”是指溶解于水中或以溶胀或可分散为小粒子的树脂或高分子物质,作为非限制性的例子包括羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)及聚乙烯吡咯烷酮(PVP)等。
“表面活性剂”是指在分子中同时具有亲水性基团和亲油性基团的物质,并且被溶解或分散在溶剂中以选择性地吸附到界面,从而显著改变界面的性质,作为非限制性的例子,包括但不限于十二烷基硫酸钠(SLS)及泊洛沙姆等。
“糖类”是指碳水化合物中相对小的分子,其可溶于水并带有甜味的化合物,作为非限制性的例子包括甘露醇及麦芽糖醇。
“非水溶性高分子”是指在水中不溶解或不溶胀的高分子物质,作为非限制性的例子包括乙基纤维素及醋酸纤维素等。
“蜡类似脂质”是指具有与蜡类似的性质的脂质,作为非限制性的例子,包括甘油基脂肪酸酯及脂肪酸聚乙二醇甘油酯等。
以上,在无特别的限制的前提下,在本说明书中提到的包括“水溶性高分子”、“表面活性剂”、“糖类”、“非水溶性高分子”及“蜡类似脂质”的各种添加剂的具体成分可在HANDBOOK OF PHARMACEUTICAL EXCIPIENTS等中公开的在药剂学上可添加的物质中适宜选择。
[包含塞来昔布的第一区域]
第一区域包含选自水溶性高分子、表面活性剂及糖类中的一种以上。
作为水溶性高分子优选选择羟丙基纤维素、羟丙基甲基纤维素及乙烯基吡咯烷酮乙酸乙烯酯共聚物中的一种以上,尤其,优选羟丙基纤维素。作为表面活性剂优选包含选自聚氧甘油酯、聚氧乙烯山梨糖醇酐脂肪酸酯、月桂基硫酸钠、甘油基脂肪酸酯、脂肪酸聚乙二醇甘油酯、二乙二醇单乙醚及蔗糖脂肪酸酯中的一种以上。糖类优选包含选自甘露醇、麦芽糖醇、乳糖醇、核糖醇、肌醇、木糖醇、麦芽三糖醇及葡萄糖中的一种以上。
在此情况下,优选地,相对于第一区域的总重量,包含0.1~20重量百分比的水溶性高分子和表面活性剂。在超出上述含量范围的情况下,塞来昔布的溶出率可大约降低10%以上。尤其,当表面活性剂的含量不满足下限和上限时,可以显著降低约10%以上的表面活性剂力。
优选地,相对于第一区域的总重量,包含10~50重量百分比的糖类。在糖类的含量不满足上述下限和上限的情况下,可能无法充分溶解塞来昔布,并且可能发生压片性或片剂的大小增加的问题。.
在不影响本发明所期望的效果的范围内,第一区域可以适宜选择包含适量的其他已知的添加剂。
[包含曲马多的第二区域]
一般而言,作为延迟药物释放的方法有用非水溶性物质包衣药物或将药物分散在对于水具有非水溶性且水分渗透性的基质物质内。在此情况下,非水溶性物质包括白蜂蜡,巴西棕榈蜡、虫胶、纤维素衍生物、单硬脂酸甘油酯、三硬脂酸甘油酯或合成水凝胶等。
并且,间或如韩国授权专利公报第10-1455741号中所述,可以通过与水接触来形成水凝胶,从而使用作为凝胶形成物质的羟丙基纤维素、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠等的纤维素衍生物或羧乙烯聚合物力来延迟药物的释放。
然而,本发明人发现,在已知的上述物质的情况下,优选地,可缓释曲马多本身,但是当在一个单一剂型内与第一区域相接处时,可引起与第一区域的相互作用,从而对塞来昔布的溶解产生不利影响。
为此,投入新处方研究的本发明人惊奇地发现特定非水溶性物对第一区域中的塞来昔布的释放模式产生的影响较小,并且与单纯地选择非水溶性物质一种类以上的情况相比,将特定非水溶性物质和蜡类似脂质进行配合是实现第一区域和第二区域的各药物所期望的释放模式的最优选的。
第二区域包括作为非水溶性物质的非水溶性高分子以及蜡类似脂质。
作为非水溶性高分子,优选地,选自纤维素类中的一种以上,最优选地,选自乙基纤维素中的一种以上。
作为蜡类似脂质,优选地,选自硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸棕榈酸甘油酯、脂肪酸聚乙二醇甘油酯、二乙二醇单乙醚、单辛酸甘油酯及氢化蓖麻油中的一种以上。
在此情况下,优选地,相对于第二区域的总重量,包含1~60重量百分比的蜡类似脂质及非水溶性高分子。在不满足上述上限和下限的情况下,则有可能在12~24小时内无法实现药物释放。
在不影响本发明所期望的效果的范围内,第二区域可以适宜选择包含适量的其他已知的添加剂。
[剂型]
作为非限制性的例子,最终的剂型可选自干压包衣片,由内核和外层构成,上述内核由缓释型区域形成,上述外层由速释型区域形成;胶囊,包含由缓释型区域形成的粒子、颗粒、微粒或片剂和由速释型区域形成的粒子、颗粒、微粒或片剂;或多层片剂,通过层压由缓释型区域形成的层和由速释型区域形成的层形成。
其中,当要剂型化为多层片剂时,可将第一区域和第二区域层压并压片。
[用法、用量]
通常,塞来昔布的用量为每次200mg,每日一次,因此市售的单剂有包含100mg的塞来昔布的产品和包含200mg的塞来昔布的产品,曲马多有多种用量,但通常为每次100~200mg,每日一次,因此市售的制剂有包含50mg的曲马多的产品和包含100mg的曲马多的产品。
根据本发明的复合剂可以设计成多种剂量并且可以以适当的方式服用,但是根据本发明的一实例,为了期待如下的效果,即,塞来昔布由增容的速释层形成,以期待初始减少疼痛效果,曲马多由缓释的缓释层形成,以期待减少副作用及止痛持续效果,将每制剂的各种药物的含量设置为200mg的塞来昔布和100mg的曲马多,这种复合剂即使每天服用一次,也可以期待令人满意的止痛效果。
如本发明的一实例所述,若在每日服用一次的复合剂中将曲马多的含量设定为100mg,则由于与塞来昔布的协同效果,即使少量也具有充分的去痛效果,且重点是有可减少与曲马多相关的副作用的优点。
但是,上述用法、用量只是一个优选实例,本发明的范围不限于此。
具体实施方式
以下,将通过实施例来说明本发明。另一方面,应该注意的是,这些实施例并不以任何方式限制本发明。
[基本条件]
本实施例中使用的赛来昔布是包含10~15μm的D90,包含4~7μm的D50的原料。
“200mg的塞来昔布胶囊”和“100mg的盐酸曲马多(Tridol)缓释片剂”分别指市售中的塞来昔布和曲马多的单剂。
本实施例中所使用的产品名称的大致主要成分如下。
表1
[实施例1]将难溶性药物增容后剂型化
实施例1-1)利用水溶性高分子及表面活性剂和糖类的处方—确认根据水溶性高分子及表面活性剂的比率的溶出形态:利用塞来昔布和下述赋形剂,以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外(in vitro)溶出试验。
表2
仅将表2的塞来昔布颗粒(颗粒物)填充到胶囊中,进行溶出评价,其结果如下表3及图1。
表3
实施例1-2)利用水溶性高分子及表面活性剂和糖类的处方—确认根据糖类的量的溶出形态:利用塞来昔布和下述赋形剂,以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外溶出试验。
表4
仅将表4的塞来昔布颗粒(颗粒物)填充到胶囊中,进行溶出评价,其结果如下表5及图2。
表5
将表4的塞来昔布颗粒物进行后混合,并压片为片剂后,进行溶出评价,其结果如下表6及图3所示。
表6
利用塞来昔布和下述赋形剂,以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外溶出试验。
表7
将表7的塞来昔布颗粒物进行后混合,并压片为片剂后,进行溶出评价,其结果如下表8及图4所示。
表8
实施例1-3)利用水溶性高分子及表面活性剂和糖类的处方—作为水溶性高分子使用羟丙基甲基纤维素(HPMC),并确认根据表面活性剂的种类的溶出形态:利用塞来昔布和下述赋形剂,以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外溶出试验。
表9
将表9的塞来昔布颗粒物进行后混合,并压片为片剂后,进行溶出评价,其结果如下表10及图5所示。
表10
实施例1-4)利用水溶性高分子及表面活性剂和糖类的处方—作为表面活性剂使用Sugar-ester P-1570以及作为糖类使用甘露醇,并确认根据水溶性高分子的种类的溶出形态:利用塞来昔布和下述赋形剂,以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外溶出试验。
表11
将表11的塞来昔布颗粒物进行后混合,并压片为片剂后,进行溶出评价,其结果如下表12及图6所示。
表12
实施例1-5)利用水溶性高分子及表面活性剂和糖类的处方-作为水溶性高分子使用羟丙基甲基纤维素(HPMC)以及作为表面活性剂使用糖酯(Sugar ester),并确认根据糖类的种类的溶出形态差:利用塞来昔布和下述赋形剂,以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外溶出试验。
表13
将表13的塞来昔布颗粒物进行后混合,并压片为片剂后,进行溶出评价,其结果如下表14及图7所示。
表14
[实施例2]水溶性药物的缓释化
以下表中的YYC-301-1-(59+XX)是指层压表25的塞来昔布区域YYC-301-1-59与曲马多区域YYC-301-1-XX的双层片。
实施例2-1)利用乙基纤维素(Ethylcellulose)和蜡类似脂质赋形剂的处方—确认根据蜡类似脂质赋形剂的量的溶出形态差:利用盐酸曲马多和下述赋形剂,以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外溶出试验。
表15
表15的溶出评价结果如下表16及图8所示。
表16
实施例2-2)利用乙基纤维素和蜡类似脂质赋形剂的处方—确认根据乙基纤维素的量的溶出形态差:利用盐酸曲马多和下述赋形剂,以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外溶出试验。
表17
上述表17的溶出评价结果如下表18及图9所示。
表18
实施例2-3)利用乙基纤维素和蜡类似脂质赋形剂的处方—确认根据蜡类似脂质赋形剂的种类的溶出形态:利用盐酸曲马多和下述赋形剂,以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外溶出试验。
表19
上述表19的溶出评价结果如下表20及图10所示。
表20
实施例2-4)利用蜡类似脂质赋形剂的处方—确认根据MCC及Lubritab(氢化蓖麻油)的比率的溶出形态:利用盐酸曲马多和下述赋形剂,以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外溶出试验。
表21
上述表21的溶出评价结果如表22及图11所示。
表22
[实施例3]水溶性基质的塞来昔布溶出干扰的例
利用以下赋形剂将盐酸曲马多和塞来昔布分别以湿式颗粒形态进行联合、干燥、制粒、混合并进行纯化,并进行体外溶出试验。
表23
曲马多处方
表25
根据本发明的一实例中的塞来昔布处方
溶出评价结果如下表26、表27、图12及图13。
表26
表27
Claims (10)
1.一种药剂学组合物,包含第一区域以及第二区域,上述第一区域包含塞来昔布,上述第二区域包含曲马多,其中,第二区域包含非水溶性高分子及蜡类似脂质。
2.根据权利要求1所述的药剂学组合物,其中,第一区域包含选自水溶性高分子、表面活性剂及糖类中的一种以上。
3.根据权利要求2所述的药剂学组合物,其中,水溶性高分子为选自羟丙基纤维素、羟丙基甲基纤维素及乙烯基吡咯烷酮乙酸乙烯酯共聚物中的一种以上。
4.根据权利要求2所述的药剂学组合物,其中,表面活性剂包含选自聚氧甘油酯、聚氧乙烯山梨糖醇酐脂肪酸酯、月桂基硫酸钠、甘油基脂肪酸酯、脂肪酸聚乙二醇甘油酯、二乙二醇单乙醚及蔗糖脂肪酸酯中的一种以上。
5.根据权利要求2所述的药剂学组合物,其中,相对于第一区域的总重量,包含0.1~20重量百分比的水溶性高分子和表面活性剂。
6.根据权利要求2所述的药剂学组合物,其中,糖类包含选自甘露醇、麦芽糖醇、乳糖醇、核糖醇、肌醇、木糖醇、麦芽三糖醇及葡萄糖中的一种以上。
7.根据权利要求2所述的药剂学组合物,其中,相对于第一区域的总重量,包含10~50重量百分比的糖类。
8.根据权利要求1所述的药剂学组合物,其中,蜡类似脂质包含选自硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸棕榈酸甘油酯、脂肪酸聚乙二醇甘油酯、二乙二醇单乙醚、单辛酸甘油酯及氢化蓖麻油中的一种以上。
9.根据权利要求1所述的药剂学组合物,其中,非水溶性高分子包含选自纤维素类中的一种以上。
10.根据权利要求1所述的药剂学组合物,其中,相对于第二区域的总重量,包含1~60重量百分比的蜡类似脂质及非水溶性高分子。
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CN112007024A (zh) * | 2019-05-28 | 2020-12-01 | 江苏恒瑞医药股份有限公司 | 艾瑞昔布与曲马多联合在制备治疗疼痛的药物中的用途 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102033716B1 (ko) * | 2017-04-03 | 2019-10-17 | 주식회사 킴스헬스케어 | 트라마돌과 셀레콕시브를 포함한 경구투여용 이중 복합정제 |
WO2018186650A2 (ko) * | 2017-04-03 | 2018-10-11 | 주식회사 킴스헬스케어 | 트라마돌과 셀레콕시브를 포함한 경구투여용 이중 복합정제 |
US20200276152A1 (en) * | 2017-09-15 | 2020-09-03 | Crystalgenomics, Inc. | Pharmaceutical composition for treating acute and chronic pain, containing polmacoxib and tramadol |
KR102631399B1 (ko) | 2018-03-30 | 2024-02-01 | 씨지인바이츠 주식회사 | 폴마콕시브 및 프레가발린을 포함하는 통증 치료용 약제학적 조성물 |
JP2020183359A (ja) * | 2019-05-09 | 2020-11-12 | 日医工株式会社 | セレコキシブ含有医薬組成物 |
WO2020252384A1 (en) * | 2019-06-14 | 2020-12-17 | Vorsanger Gary | Treatment methods utilizing oxytocin receptor agonists |
CN113521292A (zh) * | 2020-04-15 | 2021-10-22 | 江苏恒瑞医药股份有限公司 | 一种cox-2抑制剂和曲马多的复方制剂 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20080104910A (ko) * | 2007-05-29 | 2008-12-03 | 하나제약 주식회사 | 서방성 고형 제제 및 그의 제조방법 |
CN101612144A (zh) * | 2008-05-19 | 2009-12-30 | 张书毅 | 含对乙酰氨基酚和曲马多的缓释制剂 |
CN102573824A (zh) * | 2009-10-16 | 2012-07-11 | 埃斯蒂文博士实验室股份有限公司 | 治疗疼痛的包含曲马多和塞来昔布的组合物 |
KR20130069484A (ko) * | 2011-12-15 | 2013-06-26 | 주식회사 삼양바이오팜 | 세레콕시브 함유 고체분산체 및 그 제조방법 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RS49982B (sr) | 1997-09-17 | 2008-09-29 | Euro-Celtique S.A., | Sinergistička analgetička kombinacija analgetičkog opijata i inhibitora ciklooksigenaze-2 |
SA99191255B1 (ar) | 1998-11-30 | 2006-11-25 | جي دي سيرل اند كو | مركبات سيليكوكسيب celecoxib |
EP1585501A4 (en) * | 2003-01-23 | 2007-04-25 | Amorepacific Corp | PREPARATIONS OF DELAYED RELEASE AND METHOD OF MANUFACTURING THEREOF |
US20070207200A1 (en) | 2006-03-06 | 2007-09-06 | Pozen Inc. | Dosage forms for administering combinations of drugs |
PL2002828T3 (pl) | 2006-03-30 | 2019-11-29 | Nippon Zoki Pharmaceutical Co | Stały preparat farmaceutyczny |
BRPI0818762B8 (pt) * | 2007-10-16 | 2021-05-25 | Chimigen Inc | composição farmacêutica bicamada de liberação imediata e controlada contendo tramadol e acetaminofeno, e, uso de uma composição |
CA3066426A1 (en) * | 2008-01-09 | 2009-07-16 | Charleston Laboratories, Inc. | Pharmaceutical compositions comprising an antiemetic and an opioid analgesic |
CA2771539A1 (en) * | 2009-08-12 | 2011-02-17 | Valeant International (Barbados) Srl | Pharmaceutical compositions with tetrabenzine |
KR101366365B1 (ko) * | 2010-05-04 | 2014-02-21 | 주식회사 삼양바이오팜 | 트라마돌 또는 이의 약학적으로 허용 가능한 염을 포함하는 방출 제어용 약학 조성물, 및 이를 포함하는 경구용 제제 |
KR101237646B1 (ko) | 2010-12-09 | 2013-03-04 | 주식회사 드림파마 | 생체이용률이 개선된 셀레콕시브 함유 고체 분산체, 이를 포함하는 약학 조성물 및 이의 제조방법 |
KR101455901B1 (ko) | 2012-05-04 | 2014-11-03 | 성균관대학교산학협력단 | 세레콕시브 및 폴록사머를 포함하는 공융 혼합물 |
RU2607815C1 (ru) | 2012-12-20 | 2017-01-20 | РЕЙНБОУ СОУРС ЛАЗЕР (ЭрЭсЛазер) | Составной резонатор эксимерного лазера |
MX362435B (es) * | 2013-08-02 | 2019-01-17 | Laboratorio Raam De Sahuayo S A De C V | Novedoso sistema farmaceutico de entrega bifasica para el tratamiento del dolor y la inflamacion. |
-
2015
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2016
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20080104910A (ko) * | 2007-05-29 | 2008-12-03 | 하나제약 주식회사 | 서방성 고형 제제 및 그의 제조방법 |
CN101612144A (zh) * | 2008-05-19 | 2009-12-30 | 张书毅 | 含对乙酰氨基酚和曲马多的缓释制剂 |
CN102573824A (zh) * | 2009-10-16 | 2012-07-11 | 埃斯蒂文博士实验室股份有限公司 | 治疗疼痛的包含曲马多和塞来昔布的组合物 |
KR20130069484A (ko) * | 2011-12-15 | 2013-06-26 | 주식회사 삼양바이오팜 | 세레콕시브 함유 고체분산체 및 그 제조방법 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112007024A (zh) * | 2019-05-28 | 2020-12-01 | 江苏恒瑞医药股份有限公司 | 艾瑞昔布与曲马多联合在制备治疗疼痛的药物中的用途 |
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